Photoreactive drugs are unique compounds which are inactive until exposed to light of a specific wavelength. Photodynamic therapy begins with the intravenous administration of a selected photoreactive drug to a patient. At first, the drug disperses throughout the body and is taken up by most cells, whether normal or not. After a period of time usually between 3 and 48 hours, the drug clears from most normal tissue and is retained to a greater degree by hyperproliferating or otherwise abnormal cells.
Photodynamic activity begins when the photosensitizer is exposed to light of a specific wavelength. This light, usually but not necessarily generated by a laser and transmitted through a specially designed fiber optic, activates the intracellular drug. Activation results in the formation of cytotoxic species (free radicals and/or singlet oxygen) which rapidly and selectively destroy the cells in which the photosensitizer is located. Certain wavelengths of light are optimal for therapeutic destruction of rapidly proliferating cells, while other wavelengths induce a visible fluorescence and are therefore ideal for diagnostic identification of these cells.
A new generation of photosensitizers is currently under investigation or development for use in photodynamic therapy. These include chlorins (such as benzoporphyrin derivatives), purpurins, and phthalocyanines, all of which have strong hydrophobic characteristics. Extensive animal studies have shown that such poorly water-soluble pyrrole-derived macrocycles tend to maximize both diagnostic and therapeutic specificity by virtue of a high retention differential between abnormal and normal cells. While the water solubility of porphyrins can be enhanced by suitable derivatization, a significant loss of tissue specificity may occur. Therefore, simple aqueous/alcohol solutions of relatively water-soluble pyrrole-based macrocycles have proven to be much less useful.
These new generation photosensitizers often pose serious challenges to achieving suitable formulation. For more lipophilic porphyrins, dimethylsulfoxide (DMSO)/water solutions are suitable for preliminary studies either in vitro or in vivo. However, for clinical applications, dimethylsulfoxide is not considered to be an appropriate vehicle. Micellar preparations of poorly water-soluble porphyrin derivatives may be made, using the non-ionic surfactant Cremophor EL (polyoxyethylated castor oil), but serious anaphalactoid reactions have been reported and premedication with steroids may be required. Various organic solvent mixtures (e.g. polyethylene glycol, propylene glycol, t-butanol, dimethylacetamide)will also solubilize certain lipophilic porphyrin derivatives. However, such systems are often associated with pain on injection and phlebitis, due in part to local vein irritation by the solvent and to drug precipitation upon dilution in the bloodstream. In addition, these solvents are poorly metabolizable and are associated with other undesirable toxic side effects.
In addition to hydrophobic character, these new generation porphyrins often exhibit a high tendency to form aggregates due to "sandwich style" interactions between their planar rings. Molecular aggregates hinder solubilization of crystalline drug and complicate efforts to produce particle-free formulations with adequate storage stability.
Yet another formulation difficulty is the well-documented sensitivity of many pyrrole-based macrocycles to photooxidation.
Several liposomal porphyrin formulations are in human clinical trials. These include benzoporphyrin derivative (Quadra Logic Technologies, Inc., Vancouver, B.C., Canada) and Zn-phthalocyanine (CIBA-GEIGY Ltd., Basel, Switzerland). Liposomes are submicron, hollow vesicles consisting of hydrated, synthetic phospholipids arranged in a bilayer structure. However, to the best of applicant's knowledge, there are no heat-stable oil-in-water emulsions available that are suitable for injecting poorly water-soluble photosensitizing drugs. An oil-in-water emulsion is a microscopic dispersion of oil droplets in a continuous aqueous phase with a surfactant used to stabilize the dispersed droplets.